Project Summary: ! Circadian clocks synchronize organism physiology with diverse environmental and cellular signalis. Deysnchronization of master and peripheral clocks due to disruption in sleep cycles or altered metabolic function has been implicated in the onset and progression of diseases ranging from obesity, diabetes and heart disease. Central to circadian function are two primary factors: 1) A central oscillator that is impacted by complicated feedback loops to maintain circadian rhythms. 2) Sensory proteins that function in signaling nodes within the feedback loops to integrate endogenous and environmental cues. How these sensory elements alter the complex network of feedback loops to modulate circadian function is largely unknown, leading to difficulties in developing therapeutics to target mitigate the deleterious effects of desynchronization of circadian rhythms. Difficulties primarily stem from a lack of information regarding the primary chemistry synchronizing peripheral clocks with the SCN in vertebrate systems. Herein, we leverage the fact that in plants light is the primary factor dictating sensory input to the clock in all cell types, and both plants and mammals employ members of the Period-ARNT-Singleminded (PAS) family to integrate environmental cues through stimuli-dependent reorganization of protein interaction networks. Leveraging A. thaliana as a model system we interrogate how chemical signals are integrated into the circadian clock to regulate metabolism and oxidative stress to promote organism fitness. To achieve these goals we employ a combination of biophysical, computational and in vivo methods. These aims are three fold: 1) Leverage existing crystal structures to Define global conformational responses gating stimuli-dependent protein:protein interaction networks. 2) Employ new computational strategies to identify residues that propagate sensory events throughout the protein structure to selective affect specific structural elements. Therein, we identify of allosteric variants gating light- and oxidative sensing. 3) We validate structural and allosteric variants through in vitro and in vivo assays to delineate how specific allosteric pathways alter the protein-protein interaction landscape to dictate organism physiology. Importantly, residues identified in these three aims are conserved with the Period-ARNT-Singleminded family that are targets for therapeutic intervention in diverse disease states. Thus, allosteric mechanisms identified in this proposal have broad impact to human health and physiology.